Delivery system comprising means for controlling internal pressure

ABSTRACT

The present invention is directed to an improvement in a delivery system, the system comprising a wall that surrounds an internal lumen or compartment which contains a thermo-responsive beneficial agent formulation, an expandable driving member and an optional density member, and having an exit opening, and wherein the improvement comprises a) a viscosity-inducing amount of an inert viscosity-inducing agent in the thermo-responsive beneficial agent composition for increasing the viscosity of the beneficial agent composition, and/or b) a pressure-inducing exit member in the exit opening in the wall for increasing the pressure inside the lumen.

CROSS-REFERENCE TO COPENDING APPLICATIONS

This application is a continuation-in-part of application Ser. No.07/850,087, filed Mar. 12, 1993, which is a division of application Ser.No. 07/469,861, filed Jan. 24, 1990, abandoned.

DISCLOSURE OF TECHNICAL FIELD

This invention pertains to both a novel and useful delivery system. Moreparticularly, the invention relates to an improvement in a deliverysystem wherein the system comprises a wall that surrounds an internallumen comprising a thermo-responsive beneficial agent formulation, anexpandable driving member, and an optional density member, and whereinthe improvement comprises means for governing the internal pressure ofthe delivery system, and means for increasing the thermo-responsiveformulation's viscosity.

DISCLOSURE OF BACKGROUND ART

Delivery systems for dispensing a beneficial agent to a biologicalenvironment of use are known to the prior art. For example, deliverysystems comprising a wall that surrounds an internal lumen that houses athermoresponsive formulation, an expandable driving member and a densitymember are known in U.S. Pat. Nos. 4,595,583; 4,612,186; 4,624,945;4,684,524; 4,692,336; 4,717,566; 4,717,568; 4,717,718; 4,772,474; and4,844,984 all issued to Eckenhoff, Cortese and Landrau, in U.S. Pat.Nos. 4,663,148; 4,663,149; 4,678,467; 4,716,013; 4,781,714; 4,800,056;and 4,814,180 issued to Eckenhoff, Theeuwes, and Deters, and in U.S.Pat. Nos. 4,675,174 and 4,704,118 issued to Eckenhoff. These dispensingsystems of the prior art are extraordinarily effective for deliveringbeneficial agents that are hydrophilic, hydrophobic, lipophilic orlipophobic to a biological environment of use. The delivery systemsoperate successfully for their intended use, and they can delivernumerous difficult to deliver beneficial agents at a controlled andpredictable rate. Sometimes, however, the delivery systems, when inoperation in a biological environment of use having a high pressure orhigh partial pressures of biological or other gases, exhibit a deliveryrate that is unpredictable. This is due to a low internal pressure of agas phase in the delivery system relative to an exterior higher pressureor partial pressure.

SUMMARY OF THE INVENTION

It has now been unexpectedly found that the delivery behavior ofdelivery systems of the prior art can be improved, (1) by providing ameans for increasing the interior pressure to overcome an unpredictabledelivery behavior associated with an interior low pressure, and (2) byproviding a means for increasing the viscosity of the thermo-responsiveformulation inside the delivery system.

Accordingly, it is a principle object of this invention to provide anovel and useful delivery system that overcomes the disadvantagesassociated with the prior art.

Another object of the present invention is to provide an improvement ina delivery system comprising means for establishing a high internalpressure inside a delivery system thereby providing a controlled andpredictable delivery behavior over time for the delivery system.

Another object of the present invention is to provide an improvement ina delivery system comprising a means for increasing the viscosity and/oryield stress of a thermo-responsive formulation inside the deliverysystem that cooperates with a means for increasing the internal pressureto produce a controlled and known delivery behavior over a prolongedperiod of time.

Another object of the present invention is to provide a delivery systemcomprising an internal pressure substantially equal to or greater thanits external pressure, and which delivery system delivers a beneficialagent at a rate controlled by the delivery system that is substantiallyindependent of the exterior pressure.

Another object of the present invention is to provide a delivery systemcomprising an exit port that increases the internal hydraulic resistanceto flow from the delivery system.

Another object of the present invention is to provide a delivery systemcomprising a greater inside pressure relative to the outside pressurefor compressing inside void volume and for decreasing void volume thatis gas-filled and that is formed during manufacture of a flowablebeneficial agent formulation.

Another object of the present invention is to provide a delivery systemthat delivers a beneficial agent at a more consistent and predictablerate in the widely varying conditions of a biological or other fluidenvironment.

Another object of the invention is to provide a therapeutic deliverysystem for use in ruminants that delivers a medicine, a nutrient, or abiocide at a controlled rate over time and which delivery systemcompensates for variations in the biological ruminant's environmentduring delivery from the delivery system.

Another object of the invention is to provide a therapeutic deliverysystem that can remain in the rumen of a ruminant for a prolonged periodof time substantially free of adverse influences of the rumen.

Another object of the invention is to provide a delivery systemmanufactured in the form of a drug dispensing device that isself-contained, self-starting, and self-powered in a fluid environment,is easy to use, and can be manufactured at a lesser cost, therebyincreasing the usefulness of the dispensing device particularly fortreating domestic and zoo animals.

Another object of the invention is to provide a delivery systemcomprising a temperature-sensitive composition, an expandable drivingmember, and an exit port, which exit port operates to increase theinternal pressure of the delivery system in reference to the externalpressure.

Another object of the present invention is to provide a drug deliverydevice comprising a semipermeable wall that surrounds in at least a partan internal lumen and contains a thermo-sensitive composition comprisinga compound that increases the viscosity and/or yield stress of thecomposition, and which thermo-sensitive composition contains abeneficial agent and is delivered by the combined physical-chemicaloperations of the composition melting and becoming semisolid to fluid orthe like, with the composition displaced through an exit port thatoffers resistance to flow, thereby substantially preventing andlessening a premature delivery from the device.

Another object of the invention is to provide a drug delivery systemcomprising a dense member for keeping the delivery system in an animal'srumen over time, wherein the delivery system administers compositionthat is a complete pharmaceutical dosage regimen for a prolonged periodof time, the use of which delivery system requires intervention only forthe initiation of the regimen.

Another object of the invention is to provide a drug delivery systemthat can deliver a beneficial drug contained in a thermo-responsive,lipophilic pharmaceutically acceptable carrier comprising an inertcompound that increases the viscosity and/or yield stress of thecarrier, and which carrier melts in the rumen in the presence of thermalenergy absorbed from the rumen and thereby is converted into adispensable composition that is innocuous for substantially avoidingmammalian tissue irritation and interaction with mammalian proteintissue.

Another object of the invention is to provide a delivery systemcomprising a housing containing a thermo-responsive hydrophilic orhydrophobic composition comprising insoluble to soluble drugs, and whichthermo-responsive composition in response to energy input present in thegastrointestinal tract of an animal, changes its form and becomesdispensable for operative delivery through an exit port comprising aplurality of passageways for increasing the resistance to flow of thethermo-responsive composition.

Another object of the invention is to provide a drug delivery system fordispensing a drug to a ruminant, which delivery system comprises athermoplastic wall that surrounds a lumen comprising athermo-responsive, non-aqueous composition, a dense member, and anexpandable component, and which delivery system comprises a dispensinghead that increases the internal pressure to lessen gap formation fordecreasing aberrant pumping behavior from the delivery system.

These and other objects are met by the present invention which relatesto an improvement in a delivery system, the system comprising a wallthat surrounds an internal lumen or compartment which contains athermo-responsive beneficial agent formulation, an expandable drivingmember and an optional density member, and having an exit opening, andwherein the improvement comprises a) a viscosity-inducing amount of aninert viscosity-inducing agent in the thermo-responsive beneficial agentcomposition for increasing the viscosity of the beneficial agentcomposition, and/or b) a pressure-inducing exit member in the exitopening in the wall for increasing the pressure inside the lumen.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the dispensing art from the followingdetailed description of the specification, taken in conjunction with thedrawings and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a view of a delivery system designed and manufactured foradministering orally a beneficial agent to a warm blooded animal.

FIG. 2 is an opened view of the delivery system of FIG. 1, throughsection 2--2 of the vertical length of the delivery system forillustrating the structure of the delivery system comprising a wall, athermo-responsive composition, an expandable member, a dense member, andan exit port for increasing the internal pressure of the deliverysystem.

FIGS. 3a, 3b and 3c illustrate the exit port of the delivery system seenin FIG. 2, with 3a depicting a top view, FIG. 3b a bottom view, and FIG.3c a cross-sectional view of the exit port.

FIG. 4 is an opened view of the delivery system of FIG. 1 forillustrating another embodiment of the delivery system comprising adifferent internal arrangement of the components of the delivery system.

FIG. 5 is an opened view of the delivery system depicting asemipermeable wall that surrounds a lumen comprising a differentpositioning of the internal parts that act in concert for the controlleddelivery of a beneficial agent over time.

FIG. 6 is a cross-section of the delivery system illustrating anexpandable member comprising a density member dispersed therein.

FIG. 7 is an opened view of a delivery system provided by the inventionwherein the delivery system comprises a screw-like arrangement forreleasably attaching an internal pressure-producing head to the body ofthe delivery system.

FIG. 8 is an opened view of a delivery system provided by the inventionwherein the delivery system comprises a plurality of exit ports formedin the wall of the delivery system, which exit ports are designed formaintaining a high internal pressure inside the delivery system.

FIG. 9 is an opened view of the delivery system provided by theinvention wherein the delivery system comprises an internal layer forincreasing the efficiency of the delivery system.

FIG. 10 is an opened sectional view of a delivery system depicting thedelivery system comprising means comprising a plurality of capillarylike passageways in a retaining member releasably held in the deliverysystem.

FIG. 11 is a cross-section view of a delivery system comprising a singleexit designed for maintaining an internal back pressure inside thedelivery system.

FIGS. 12 through 22 are graphs that depict the release rate pattern fordelivery systems under various testing environments.

In the drawings and in the specification, like parts in related figuresare identified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further detailed elsewhere in the disclosure.

DETAILED DISCLOSURE OF THE DRAWINGS

Turning now to the drawing figures in detail, which are examples of newand useful therapeutic delivery systems for dispensing a beneficialagent, and which examples are not to be construed as limiting, oneexample of a delivery system is depicted in FIG. 1 identified by thenumeral 10. In FIG. 1, delivery system 10 is manufactured as a dispensercomprising a body 11 formed by a wall 12 that surrounds an internallumen, not seen in FIG. 1. Delivery system 10 comprises a lead end 13for receiving an exit member, not seen in FIG. 1, and a trailing end 14.

Drawing FIG. 2 depicts an opened section the therapeutic dispensingsystem 10 of FIG. 1 through line 2--2 of FIG. 1. Therapeutic system 10of FIG. 2 comprises body 11, wall 12, lead end 13, rear end 14, andopening 15 in wall 12. Wall 12 surrounds an internal lumen orcompartment 16. Wall 12 comprises, in a presently preferred embodiment,in at least a part a semipermeable wall forming composition that issubstantially permeable to the passage of an external fluid andsubstantially impermeable to the passage of a beneficial agent and otheringredients contained in delivery system 10. In another embodiment, wall12 comprises at least in part a semipermeable composition with theremainder of the wall comprising a different composition substantiallyimpermeable to the passage of fluid and substantially impermeable to thepassage of a beneficial agent. Wall 12 is non-toxic and it maintains itsphysical and chemical integrity, that is, it doesn't erode during thedispensing period. System 10, in a presently preferred embodiment, ismanufactured with wall 12 as a single unit member, by injection molding,or the like.

Lumen 16 contains a thermo-responsive, heat-sensitive composition 17,identified by wavy lines, a beneficial agent 18, represented by dots,and an inert compound 19, represented by dashes, the inert compound 19for increasing the viscosity or the internal resistance to flow ofthermo-responsive composition 17. Lumen 16 further contains anexpandable driving member 20 that is in layered contact with acontacting surface 21 of thermo-responsive composition 17. Both thethermo-responsive composition 17 and the expandable member 20 have ashape that corresponds to the internal shape of lumen 16. Lumen 16 alsocontains a dense member or densifier 22 (also known as a densityelement) that is in contact with thermo-responsive composition 17, whichdense member 22 is positioned in lumen 16 distant from expandable member20. Dense member 22 comprises a passageway or bore 23 with an opening 24adapted for receiving in tight relationship an exit member 25, whichexit member 25 is used for increasing the internal hydraulic resistanceto flow of thermoresponsive composition 17. Dense member 22 comprises anopening 26 for letting thermo-responsive composition 17 flow from lumen16 to exit member 25 and hence to the exterior of delivery system 10.Dense member 22 is a component of delivery system 10 designed forkeeping system 10 in the rumen of an animal over a prolonged period oftime.

FIGS. 3a, 3b and 3c illustrate one presently preferred embodiment ofexit member 25. FIG. 3a is a top view of exit member 25 depicting aplurality of tiny passageways 27 surrounded by a supporting shoulder 28.Shoulder 28 receives wall 12 in a curved shoulder relation to keep exitmember 25 firmly inside lumen 16. FIG. 3b is a bottom view of exitmember 25 which view depicts an array of parallel passageways 27 sizedto produce a pressure difference across exit member 25 seen in ascreen-like arrangement, and support by the perimeter shoulder of exitmember 25. In FIG. 3a, the bottom of the shoulder also is identified bythe numeral 28. FIG. 3c is a cross-section through exit member 25 forillustrating a plurality of passageways 27. In cross-section, thepassageways can be circular, square, hexagonal or any appropriate shapethat increases the resistance to flow of the thermoresponsivecomposition 17 from delivery system 10. In section, the passageways 27can be any shape that is appropriate for economy of manufacturing orstructural strength required by a plurality of passageways consistentwith space and materials. In FIG. 3c, exit member 25 comprises ashoulder or perimeter that extends around passageways 27 and itcomprises a wall 12 receiving indentation 28a for releasably receivingand for fixing exit member 25 to wall 12 of delivery system 10, whichprevents exit member 25 from separating from delivery system 10 duringoperation of the delivery system.

Exit member 25, as seen in FIGS. 3a, 3b and 3c, is provided by theinvention to establish a state of high internal back pressure inside thedelivery system through the design of the exit member coupled with thephysical properties of the thermo-responsive composition. A highinternal pressure operates to keep any possible voids in the system fromexpanding due to gas passing into the delivery system from a surroundingruminal environment. A large volume of gas is produced during feeding bya ruminant. The ruminants have four stomach compartments, and the rumenis the largest of the four stomach compartments. In ruminants, ingestedfeed first passes into the rumen, where it is pre-digested or degradedby fermentation. During this period of fermentation, the ingested feedmay be regurgitated to the mouth for salivation and mastication. Also,gases are produced during this normal process of digestion of feed. Theruminal gas composition usually comprises 40 to 70% carbon dioxide, 20to 40% methane, 15 to 35% nitrogen, 0.1 to 0.7% oxygen, 0.1 to 0.5%hydrogen and 0.01 to 0.05% hydrogen sulfide. The rumen temperature ismaintained at a relatively constant 38 to 42 degrees C. duringfermentation, and copious salivary secretions of bicarbonate andphosphate buffer the rumen fermentations usually to a pH of between 5 to7. The total pressure in the rumen ranges from slightly below 760 mm Hgto 830 mm Hg absolute. After salivation and mastication, the partiallydigested feed is re-swallowed and ultimately finds its way through therumen and reticulum to the omasum and abomasum of the stomach forpassage through the remainder of the animal's alimentary canal duringwhich assimilation of the available food products occurs. Thecomposition of rumen gas is disclosed in Canadian Journal of AnimalScience, Vol. 41, pp 187-96, (1961); and in The Physiology of DomesticAnimals, 7th Ed., pp 382-84, (1955), published by Comstock PublishingAssociates.

In operation, gases present in the ruminal environment diffuse throughthe semipermeable wall into the lumen and diffuse into any existingvoids in the delivery system. Additionally, gases can be generatedwithin the system by the rusting or eroding of metal density elements.The voids can be unavoidably manufactured into the delivery systemduring manufacture of the expandable member, the density member, andfilling of the partition and drug formulation layers and they can growin size if the partial pressure of gas components in the void is lessthan the partial pressure of gas components in the surroundingenvironment. The gases from the permeant wall diffuse down the activitygradient into the void to reach equilibrium. Further, the severity ofthis problem is magnified by the fact that several ruminal gases diffusethrough semipermeable walls at much greater rates than the air in thevoids. If the pressure surrounding the void is high, the tendency ofexternal gases to diffuse into the void and expand will be greatlyreduced, the void will not grow and it will be squeezed into arelatively incompressible state. This invention by increasing theinternal pressure relative to the external pressure overcomes andeliminates erratic pumping rates and premature delivery attributed tovoid volume.

FIG. 4 depicts another manufacture of delivery system 10 as seen inopened section. Delivery system 10 comprises body 11, wall 12, lead end13, rear end 14, and opening 15 in wall 12. Wall 12 surrounds lumen 16.Lumen 16 contains a thermo-responsive composition 17, a beneficial agent18, and an inert compound 19 which increases the viscosity and/or yieldstress of thermo-responsive composition 17. Lumen 16 also contains adense member 22 and an expandable member 20. Delivery system 10comprises in lead end 13 an exit member 25. Exit member 25 comprises aplurality of exit passageways 27 for releasing under pressurethermo-responsive composition 17 from lumen 16. Exit member 25 comprisesa shoulder 28 that extends around the passageways 27, with wall 12overlapping onto shoulder 28 to keep exit member 25 positioned inopening 15 in wall 12. Exit member 25 functions to enhance the interiorpressure relative to the outside pressure during operation of thedelivery system, thereby (1) compressing any evolved gas voids anddecreasing the void volume in a flowable thermo-responsive composition,(2) supporting the wall internally against collapsing external forces,(3) substantially preventing diffusional and turbulent mixing of ruminalfluid contents with the thermo-responsive composition in the deliverysystem, (4) preventing, effectuating and restricting a prematuredischarge of a thermo-responsive composition from within the deliverysystem due to pressure developed within by gas evolution or temperaturechanges in storage or in transport, and (5) making the deliveryperformance of delivery system 10 more consistent and predictable underthe widely varying biological conditions of the ruminant.

The delivery system provides a consistent and predictable release ratepattern of beneficial agent delivery as seen by the following equation(for exit member passageways of circular cross section): ##EQU1##wherein ΔP is the pressure drop across the exit port, Q is thevolumetric release rate, μ is the viscosity of the thermo-responsivecomposition, L is the length of the exit port, n is the number of exitpassageways and R is the radius of the exit passageways. For example, ΔPfor a delivery system provided by the equation should exceed 1.5 psi andpreferably in the range of 2 to 100 psi, more preferably in the range of6 to 50 psi, to substantially lessen erratic pumping and prematuredelivery. The number of exit passageways can be greater than or equalto 1. Generally, for example, when a grid-like exit member is used, thenumber of exit passageways is between 1 to 200, and the radius of eachof the exit passageways is then adjusted so that the pressure drop is inthe desired range.

FIG. 5 depicts another manufacture of delivery system 10 provided by theinvention. Delivery system 10 comprises body 11, wall 12, lead end 13,rear end 14, opening 15, lumen 16, thermo-responsive composition 17,beneficial agent 18, inert viscosity-inducing compound 19, dense member22, expandable driving member 20, exit member 25, passageways 27 andshoulder 28. In the manufacture depicted, passageways 27 comprisecapillaries or small tubes in slender elongated form comprising a smallbore and held in spaced-apart order by exit member 25. In FIG. 5, thedensity member 22 is positioned between thermo-responsive composition 17and expandable member 20.

FIG. 6 depicts another manufacture provided by the invention. Thedelivery system 10 provided by the invention in this manufacturecomprises a body 11, wall 12, lead end 13, rear end 14, opening 15,lumen 16, thermoresponsive composition 17, beneficial agent 18, inertcompound 19, exit member 25, passageways 27 and shoulder 28. In FIG. 6,expandable member 20 comprises a dense member 22 dispersed throughoutexpandable member 20. In FIG. 6, exit member 25 and inert compound 19operate in combination to produce and regulate the internal pressure indelivery system 10.

FIG. 7, depicts another manufacture provided by the invention. In FIG.7, delivery system 10 comprises a body 11, a wall 12, lead end 13, rearend 14, opening 15, lumen 16, thermo-responsive composition 17,beneficial agent 18, inert compound 19, expandable driving member 20 anddense member 22. In FIG. 7, delivery system 10 is made with threads 29at the top of wall 12 for turning threads 30 of exit member 25 into thedelivery system. The mated threads act as a retaining means forreleasably holding exit member 25 in delivery system 10. In thismanufacture, delivery system 10 can be recovered, the exit member turnedtherefrom and delivery system 10 refilled for multiple use. In oneembodiment in FIG. 7, the improvement comprises exit member 25 forgoverning the internal pressure of delivery system 10 coupled withviscosity means 19 for increasing the thermo-responsive formulation'sviscosity.

FIG. 8 depicts another delivery system 10 provided by the invention. InFIG. 8, delivery system 10 comprises a body 11, a wall 12, lead end 13,rear end 14, lumen 16 comprising a thermo-responsive composition 17containing beneficial agent 18 and inert viscosity-inducing agent 19. InFIG. 8, delivery system 10 comprises an expandable driving member 20consisting of an osmagent that imbibes and absorbs fluid through wall 12to form a solution that continuously fills lumen 16 and therebydisplaces thermo-responsive composition 17 from delivery system 10.Driving member 20 comprises a densifier 22 for keeping delivery system10 in the ruminant for a prolonged period of time. In FIG. 8, deliverysystem 10 comprises a multiplicity of exit passageways 27 integrallyformed in wall 12 as an integral exit member 25 for increasing theresistance to flow of thermo-responsive composition 17 from deliverysystem 10, and for concomitantly increasing the internal pressure insidedelivery system 10.

FIG. 9 illustrates another delivery system 10 provided by the invention.In FIG. 9, delivery system 10 comprises a body 11, a wall 12, lead end13, rear end 14, opening 15, internal lumen 16, thermo-responsivecomposition 17, beneficial agent 18, inert compound 19, driving member20 and a dense member 22. In FIG. 9, thermo-responsive composition 17 isseparated from expandable member 20 by a partition lamina or layer 31.Partition layer 31 is positioned between the active thermo-formulation17 and the expandable member 20 for substantially reducing diffusion,migration, entrapment, or the like of active agent 18 in expandablemember 20. Layer 31 also protects the active agent formulation from anypossible interaction with the expandable member, thereby improving thestability of the active agent formulation. In one presently preferredembodiment, partition layer 31 is made from a soft or a flexiblepolymeric composition for aiding in pushing the maximum amount offormulation 17 containing agent 18 from delivery system 10. Thus, layer31 serves as a means for increasing the delivery efficiency of deliverysystem 10 by insuring the total force generated by expandable member 20is applied against heat-responsive formulation 17 containing agent 18,for squeezing formulation 17 through pressure-inducing exit passageways27. Partition layer 31 in operation functions like a piston, and it isso constructed to movably provide and maintain a tight piston-headarrangement between the active agent phase and the expandable phase inlumen 16. Layer 31 is frictionally disposed, but it is free to movewithin delivery system 10 by sliding, while at the same time maintainingthe operability of delivery system 10. Partition layer 31 preferablycomprises nontoxic materials.

FIG. 10 illustrates another delivery system 10 seen in opened section asprovided by this invention. In FIG. 10, delivery system 10 comprises abody 11, a wall 12, lead end 13, rear end 14, density member 22,expandable driving member 20, aperture 26 entering into bore 23extending through density member 22, interface 21, and lumen 16comprising a thermo-responsive composition 17 comprising beneficialagent 18 and inert viscosity-enhancing agent 19. In FIG. 10, deliverysystem 10 includes exit member 25 comprising a plurality of passageways27 optionally designed as a releasable perforated plate, a perforated orridged plastic or metal plate, or a plurality of capillaries forelevating the pressure inside dosage system 10. The capillaries in onemanufacture comprise a number of slender elongated tubes comprising avery small bore for decreasing the flow rate from delivery system 10. Apassageway-retaining member 32 releasably holds pressure-inducingpassageways 27 in delivery system 10 during the beneficial agent 18releasing period.

FIG. 11 illustrates another delivery system 10 seen in opened section asprovided by this invention. In FIG. 11, delivery system 10 comprises abody 11, a wall 12, lead end 13, rear end 14, density member 22,expandable driving member 20, aperture 26 entering into capillary 33 ofdensity member 22, interface 21, and lumen 16 containingthermo-responsive composition 17 comprising beneficial agent 18 andinert viscosity-inducing agent 19. In FIG. 11, delivery system 10comprises a single passageway 33 for (a) increasing the internalpressure of delivery system 10, for (b) restricting drug flow fromdelivery system 10 and for (c) acting simultaneously with inertviscosity-inducing agent 19 for restricting drug flow from deliverysystem 10. FIG. 11 depicts an optional embodiment comprising a singleexit passageway. A single passageway can be used with the proviso thatits cross-sectional area functions as a means for pressurizing lumen 16of delivery system 10 and as a means for controlling the flow rate ofbeneficial agent 18 from lumen 16.

While FIGS. 1-11 illustrate various delivery devices 10 that can be madeaccording to the invention, it is to be understood that these deliverydevices are not to be contrued as limiting the invention, as thedelivery device designed as a dispenser can take other shapes, sizes andforms for delivering beneficial agents to a fluid environment of use.While the Figures all illustrate the presence of a density element, suchdensity element is not critical to the invention, and devices accordingto the present invention without a density element are contemplated.Such devices are particularly suitable as implants for use with humansor animals.

The presently preferred environment of use is the rumen of a ruminantanimal. However, the devices are not restricted to use in ruminantanimals or to a rumen as an environment of use. Long-term dispensingdevices of the invention find use, for example, in humans or otheranimals. The environment of use can comprise a body cavity such as theperitoneum, vagina, or intestinal tract. The devices may also beutilized as a subcutaneous implant. A single dispensing device orseveral dispensing devices can be administered to a subject during atherapeutic program.

The delivery system 10 as provided by the invention can be manufacturedin a variety of sizes and shapes for use with ruminant animals. Onepresently preferred shape is a cylinder-like shape. For example, for usewith sheep, delivery system 10 can embrace a capsule-like shapecomprising a diameter of about 0.5 inches to 1 inch (1.3 cm to 2.5 cm)and a length of about 0.5 inches to 2.5 inches (1.3 cm to 6.6 cm). Foruse with cattle, delivery system 10 has a diameter of about 0.5 inchesto 1.5 inches (1.3 cm to 3.8 cm), and a length of about 1 inch to 4inches (2.5 cm to 10 cm).

The delivery system of the present invention operates to deliver abeneficial agent 18 to a fluidic environment of use by a combination ofthermodynamic and kinetic integrally performed activities. That is, inoperation, thermo-responsive heat-sensitive composition 17, in responseto the temperature of the environment, absorbs thermal energy, melts andforms a flowable, or a ribbon-like, semi-paste deliverable compositionfor delivering beneficial agent 18 through pressure-inducing exitpassageways 27 in an exit member 25. As composition 17 melts,concomitantly therewith external fluid is imbibed through semipermeablewall 12 by driving member 20, comprising an expandable hydrogel and/oran osmagent composition. The fluid imbibed into the hydrogel causes itto continuously expand and swell, or the imbibed fluid causes theosmagent composition to continuously form a solution, which expansion orsolution, in either operation, pushes and displaces thermoresponsivecomposition 17 from delivery system 10. The driving member 20, in apreferred embodiment, operates while maintaining an intact immiscibleboundary, as seen in FIG. 2 at interface 21, defined by heat-sensitivecomposition 17 and driving member 20. When the environment is a rumen,dense member 22 in delivery system 10 functions to keep the deliverysystem in the rumen. Delivery system 10 is able to deliver beneficialagent 18 at a controlled rate over a prolonged period of time, usually 1day to about 180 days, or longer, and in a presently preferredembodiment is at least about 20 days.

While FIGS. 1 through 12 illustrate various delivery systems 10 that canbe made according to the invention, it is to be understood thesedelivery systems are not to be construed as limiting the invention, asthe delivery system designed as a dispenser can take other shapes, sizesand forms for delivering beneficial agents to a fluid environment ofuse. The delivery system can be used in hospitals, veterinary clinics,homes, farms, zoos, outpatient clinics, laboratories, on the range, infeed lots, for administering a drug to a warm-blooded animal includinghumans, and in other environments of use.

DETAILED DISCLOSURE OF THE INVENTION

In accordance with the practice of this invention, it has now been foundwall 12 of delivery system 10 comprises in at least a part asemipermeable polymeric composition comprising semipermeable homopolymercompositions, semipermeable copolymer compositions, a compositioncomprising blends of polymers, and the like. Representative polymericmaterials comprise cellulose monoesters, cellulose diesters, cellulosetriesters, cellulose ethers, cellulose ester-ethers, mixtures thereof,and the like. The cellulosic polymers have a degree of substitution, ontheir anhydroglucose unit from greater than 0 up to 3 inclusive. Theexpression degree of substitution means the average number of hydroxylgroups originally present on the anhydroglucose unit that are replacedby a substituting group, or converted into another group. Theanhydroglucose unit can be partially or completely substituted withgroups such as acyl, alkanoyl, aroyl, alkyl, alkenyl, alkoxyl, halogen,carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate,alkylsulfamate, and like semipermeable polymer forming groups.

The semipermeable polymers typically comprise a member selected from thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di-, and tri-alkenylates, mono-, di- andtri-aroylates, and the like. Exemplary polymers include celluloseacetate having a D.S. of 1.8 to 2.3 and an acetyl content of 32 to39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl contentof 21 to 35%; cellulose triacetate having a D.S. of 2 to 3 and an acetylcontent of 34 to 44.8%; and the like. More specific cellulosic polymerscomprise cellulose propionate comprising a D.S. of 1.8 and a propionylcontent of 38.5%; cellulose acetate propionate having an acetyl contentof 2.5 to 3%, an average propionyl content of 39.2 to 45% and a hydroxylcontent of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8,an acetyl content of 13 to 15%, and a butyryl content of 34 to 39%;cellulose acetate butyrate having an acetyl content of 2 to 32.0% andpreferably of 29.1 to 31%, a butyryl content of 16 to 53% and preferablyof 16.5 to 18.2%, and a hydroxyl content of 0.5 to 4.7% and preferablyof 0.4 to 1%; cellulose triacylates having a 0.5. of 2.9 to 3 such ascellulose trivalerate, cellulose trilaurate, cellulose tripalmitate,cellulose trioctanoate, and cellulose tripropionate; cellulose diestershaving a 0.5. of 2.2 to 2.6 such as cellulose disuccinate, cellulosedipalmitate, cellulose dioctanoate, cellulose dicarpylate; cellulosepropionate morphino-butyrate; cellulose acetate butyrate; celluloseacetate phthalate; and the like; mixed cellulose esters such ascellulose acetate valerate; cellulose acetate succinate, cellulosepropionate succinate, cellulose acetate octanoate, cellulose valeratepalmitate, cellulose acetate heptonate, and the like. Semipermeablepolymers are known in U.S. Pat. No. 4,077,407, and they can besynthesized by procedures described in Encyclopedia of Polymer Scienceand Technology, Vol. 3, pp 325-354, 1964, published by IntersciencePublishers, Inc., New York.

Additional semipermeable polymers comprise cellulose acetalaldehydedimethyl cellulose acetate; cellulose acetate ethylcarbamate; celluloseacetate methylcarbamate; cellulose dimethylaminoacetate; a cellulosecomposition comprising cellulose acetate andhydroxypropylmethylcellulose; a composition comprising cellulose acetateand cellulose acetate butyrate; a cellulose composition comprisingcellulose acetate butyrate and hydroxypropyl methyl cellulose;semipermeable polyamides; semipermeable polyurethanes; semi permeablepolysulfones; semipermeable sulfonated polystyrenes; cross-linked,selectively semipermeable polymers formed by the coprecipitation of apolyaninon and a polycation as disclosed in U.S. Pat. Nos. 3,173,876;3,276,586; 3,541,005; 3,541,006; and 3,546,142; selectivelysemipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable polystyrene derivatives; semipermeablepoly(sodium styrenesulfonate); semipermeable poly(vinylbenzyltrimethyl)ammonium chloride; semipermeable polymers exhibiting a fluidpermeability of 10⁻¹ to 10⁻⁷ (cc·mil/cm² hr·atm) expressed as peratmosphere of hydrostatic or osmotic pressure difference across asemipermeable wall. The polymers are known to the art in U.S. Pat. Nos.3,845,770; 3,916,899 and 4,160,020, and in Handbook Of Common Polymers,by Scott, J. R. and Roff, W. J., 1971, published by CRC Press,Cleveland, Ohio.

Wall 12 also can comprise a flux-regulating agent. A flux regulatoryagent is added to wall 12 compositions to assist regulating the fluidpermeability of fluid through the wall. The flux-regulating agent can bepreselected to increase or decrease the liquid flux. Agents that producea marked increase in permeability to fluid such as water or biologicalfluids are often essentially hydrophilic, while those that produce amarked decrease to fluids such as water or biological fluids areessentially hydrophobic. The amount of regulator in the wall, whenincorporated therein, generally is from about 0.01% to 30% by weight ormore. The flux regulator agents in one embodiment that increase fluxinclude polyhydric alcohols, polyalkylene glycols, polyalkylenediols,polyesters of alkylene glycols, and the like. Typical flux enhancersinclude polyethylene glycol 300, 400, 600, 1500, 4000, 6000 and thelike; low molecular weight glycols such as polypropylene glycol,polybutylene glycol and polyamylene glycol; the polyalkylenediols suchas poly(1,3-propanediol), poly(1,4-butanediol), poly(1,6-hexanediol),and the like; aliphatic diols such as 1,3-butylene glycol,1,4-pentamethylene glycol, 1,4-hexamethylene glycol, and the like;alkylene triols such as glycerine, 1,2,3-butanetriol, 1,2,4-hexanetriol,1,3,6-hexanetriol and the like; ester such as ethylene glycoldiproprionate, ethylene glycol butyrate, butylene glycol dipropionate,glycerol acetate esters, and the like. Representative flux decreasingagents include phthalates substituted with an alkyl, an alkoxy or withboth an alkyl and alkoxy group such as diethyl phthalate, dimethoxyethylphthalate, dimethyl phthalate, and di(2-ethylhexyl)phthalate; arylphthalates such as triphenyl phthalate, and butyl benzyl phthalate;insoluble salts such as calcium sulphate, barium sulphate, calciumphosphate, and the like; insoluble oxides such as titanium oxide;polymers in powder, granule and like form such as polystyrene,polymethylmethacrylate, polycarbonate, and polysulfone; esters such ascitric acid esters esterified with long chain alkyl groups; inert andsubstantially water impermeable fillers; resins compatible withcellulose based wall forming materials; and the like.

Other materials that can be used to provide wall 12 for impartingflexibility and elongation properties to the wall, for making the wallless to nonbrittle and to render tear strength include phthalateplasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octylphthalate, straight, chain phthalates of six to eleven carbons,diisononyl phthalate, diisodecyl phthalate, and the like. Theplasticizers include nonphthalates such as triacetin, triisononyltimellitate, sucrose acetate isobutyrate, epoxidized soybean oil,tributyl citrate, triethyl citrate and the like. The amount ofplasticizer in a wall when incorporated therein is about 0.01% to 20% byweight, or higher.

Expandable driving member 20 has a shape that corresponds to the^(I)internal shape of wall 12 and compartment 16 and is made from a hydrogelcomposition, or from an osmagent composition, or from a mixture of anosmagent and an osmopolymer. The hydrogel composition is noncross-linkedor optionally cross-linked and it possesses osmotic properties, such asthe ability to imbibe an exterior fluid through semipermeable wall 12,and exhibit an osmotic pressure gradient across semipermeable wall 12against a fluid outside delivery system 10. The materials used forforming the swellable, expandable member, are polymeric materials neat,and polymeric materials blended with osmotic agents that interact withwater or a biological fluid, absorb the fluid and swell or expand to anequilibrium state. The polymer exhibits the ability to retain asignificant fraction of imbibed fluid in the polymer molecularstructure. The polymers in a preferred embodiment are gel polymers thatcan swell or expand to a very high degree, usually exhibiting a 2 to 50fold volume increase. The swellable, hydrophilic polymers, also known asosmopolymers can be noncross-linked or lightly cross-linked. Thecross-links can be covalent or ionic bonds with the polymer possessingthe ability to swell in the presence of fluid, and when cross-linked itwill not dissolve in the fluid. The polymer can be of plant, animal orsynthetic origin. Polymeric materials useful for the present purposecomprises poly(hydroxyalkyl methacrylate) having a molecular weight offrom 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecularweight of from 10,000 to 360,000; anionic and cationic hydrogels;poly(electrolyte) complexes; poly(vinyl alcohol) having a low acetateresidual; a swellable mixture of agar and carboxymethyl cellulose; aswellable composition comprising methyl cellulose mixed with a sparinglycross-linked agar; a water-swellable copolymer produced by a dispersionof finely divided copolymer of maleic anhydride with styrene, ethylene,propylene, or isobutylene; water swellable polymer of N-vinyl lactams;and the like.

Other gellable, fluid-imbibing and -retaining hydrogel, hydrophilicpolymers useful for forming the hydrophilic, expandable driving member20 include pectin having a molecular weight ranging from 30,000 to300,000; polysaccharides such as agar, acacia, karaya, tragacanth,algins and guar; Carbopol® acidic carboxy polymer and its saltderivatives; polyacrylamides; water-swellable indene maleic anhydridepolymers; Good-rite® polyacrylic acid having a molecular weight of80,000 to 200,000; Polyox® polyethylene oxide polymers having amolecular weight of 100,000 to 5,000,000; starch graft copolymers;AquaKeep® acrylate polymers with water absorbability of about 400 timesits original weight; diesters of polyglucan; a mixture of cross-linkedpolyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); zein available asprolamine; poly(ethylene glycol) having a molecular weight of 4,000 to100,000; and the like. In a preferred embodiment, the expandable member20 is formed from polymers and polymeric compositions that arethermoformable. Representative polymers possessing hydrophilicproperties are known in U.S. Pat. Nos. 3,865,108; 4,002,173; 4,207,893;4,327,725, and in Handbook of Common Polymers; by Scott and Roff,published by Cleveland Rubber Company, Cleveland, Ohio.

The swellable, expandable polymer 20, in addition to providing a drivingsource for delivering a beneficial agent 18 from the dispenser 10,further serves to function as a supporting matrix for an osmoticallyeffective solute, also known as an osmagent. The osmotic solute can behomogeneously or heterogeneously blended with the polymer to yield thedesired expandable member 20. The composition in a presently preferredembodiment comprises at least one polymer and at least one osmoticsolute. Generally, a composition will comprise about 20% to 95% byweight of polymer and 80% to 5% by weight of osmotic solute, with apresently preferred composition comprising 35% to 75% by weight ofpolymer and 65% to 25% by weight of osmotic solute with the total weightof the composition equal to 100% by weight.

The osmagent that can be used neat or blended homogeneously orheterogeneously with the swellable polymer 20 to form a push member arethe osmotically effective solutes that are soluble in the fluid imbibedinto the swellable polymer, and exhibit an osmotic pressure gradientacross the semipermeable wall against an exterior fluid. Expandablemember 20, in another embodiment, comprises an osmagent as the drivingmember for displacing the thermo-responsive composition from deliverysystem 10. In this embodiment, a compressed tablet comprising anosmagent is shaped for placement in lumen 16 for displacing thethermo-responsive composition from delivery system 10. Representative ofosmotically effective osmagents that can be blended with the hydrogel,or used to provide an osmotic driving tablet comprise magnesium sulfate,magnesium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose,potassium chloride, glucose, and the like. The osmotic pressure inatmospheres, ATM, of the osmagents suitable for the invention will begreater than zero ATM, generally from eight ATM up to 500 ATM, orhigher.

The thermo-responsive composition 17, comprising agent 18 homogeneouslyor heterogeneously dispersed or dissolved therein, in a presentlypreferred embodiment is a heat-sensitive, hydrophilic or hydrophobiccomposition that exhibits solid-like properties at room temperature of21° C. to 25° C., and within a few centigrade degrees thereof, andexhibits in a preferred embodiment a melting point that approximatesmammalian body temperatures, and within a few centigrade degreesthereof. The present invention uses the phrases "melting point","softening point", "pour point", or "liquifies" to indicate thetemperature at which the thermo-responsive composition melts, undergoesdissolution, or forms a paste-like ribbon, dissolves to form adispensable carrier so it can be used for dispensing agent 18 fromdelivery system 10.

The term "thermo-responsive composition 17" as used for the purpose ofthis invention includes thermoplastic compositions capable of softening,or becoming dispensable in response to heat and hardening again whencooled. The term also includes thermotropic compositions capable ofundergoing change in response to the application of energy in a gradientmanner. These thermo-responsive compositions 17 are temperaturesensitive in their response to the application or withdrawal of energy.The term "thermo-responsive" as used for the purpose of this inventionin a preferred embodiment denotes the physical-chemical composition toexhibit solid, or solid-like properties at temperatures of 21° C. to 25°C. and usually up to 31° C., and become fluid, semisolid, or viscouswhen disturbed by heat at temperatures from 31° C., usually in the rangeof 31° C. to 45° C. and more preferably at mammalian body temperaturesof 37° C. to 42° C. Thermo-responsive carrier 17 is heat-sensitive andpreferably anhydrous and it possesses the properties for melting,dissolving, undergoing dissolution, softening, or liquefying at theelevated temperatures, thereby making it possible for the dispenser 10to deliver the thermo-responsive carrier with the beneficial agent 18homogeneously or heterogeneously blended therein. The thermo-responsivecarrier can be lipophilic, hydrophilic or hydrophobic. Another importantproperty of the carrier is its ability to maintain the stability of theagent contained therein during storage and during delivery of the agent.Representative thermo-responsive compositions and their melting pointsare as follows: cocoa butter 32°-34° C.; cocoa butter plus 2% beeswax35°-37° C.; propylene glycol monostearate and distearate 32°-35° C.;hydrogenated oils such as hydrogenated vegetable oil 36°-37.5° C.; 80%hydrogenated vegetable oil and 20% sorbitan monopalmitate 39°-39.5%; 80%hydrogenated vegetable oil and 20% polysorbate 60, 36°-37° C.; 77.5%hydrogenated vegetable oil, 20% sorbitan trioleate and 2.5% beeswax35°-36° C.; 72.5% hydrogenated vegetable oil, 20% sorbitan trioleate,2.5% beeswax and 5.0% distilled water, 37°-38° C.; mono-, di-, andtriglycerides of acids having from 8-22 carbon atoms including saturatedand unsaturated acids such as palmitic, stearic, oleic, linoleic,linolenic and arachidonic; glycerides of fatty acids having a meltingpoint of at least 32° C. such as monoglycerides, diglycerides andtriglycerides of vegetable fatty acids having 10 to 18 carbon atomsobtained from coconut oil, olive oil and the like; partiallyhydrogenated cottonseed oil 35°-39° C.; hardened fatty alcohols and fats33°-36° C.; hexadienol and hydrous lanolin triethanolamine glycerylmonostearate 38° C.; eutectic mixtures of mono-, di-, and triglycerides35°-39° C.; Witepsol® #15, triglyceride of saturated vegetable fattyacid with monoglycerides 33.5°-35.5° C.; Witepsol® H32 free of hydroxylgroups 31°-33° C.; Witepsol® W25 having a saponification value of225-240 and a melting point of 33.5°-35.5° C.; Witepsol™ E75 having asaponification value of 220-230 and a melting point of 37°-39° C.; apolyalkylene glycol such as polyethylene glycol 1000, a linear polymerof ethylene oxide, 38°-41° C.; polyethylene glycol 1500, melting at38°-41° C.; polyethylene glycol monostearate 39°-42.5° C.; 33%polyethylene glycol 1500, 47% polyethylene glycol 6000 and 20% distilledwater 39°-41° C.; 30% polyethylene glycol 1500, 40% polyethylene glycol4000 and 30% polyethylene glycol 400, 33°-38° C.; mixture of mono-, di-,and triglycerides of saturated fatty acids having 11 to 17 carbon atoms,33°-35° C.; block polymer of 1,2-butylene oxide and ethylene oxide;block polymer of propylene oxide and ethylene oxide; block polymer ofpolyoxyalkylene and propylene glycol; microcrystalline waxes that becomesemisolid at 37° C., and the like. The thermo-responsive composition isa means for storing a beneficial agent in a solid composition at atemperature of 20°-32° C., maintaining an immiscible boundary at theswelling composition interface, and for dispensing the agent in aflowable composition at a temperature greater than 32° C., andpreferably in the range of 32°-40° C. The thermo-responsive compositionon being dispensed into a biological environment are easily excreted,metabolized, assimilated, or the like, for effective use of thebeneficial agent.

The term "beneficial agent 18" as used herein includes medicines ordrugs, nutrients, vitamins, food supplements and other agents thatbenefit an animal, including a warm-blooded animal, and humans, and in apresently preferred embodiment a ruminant animal. The beneficial agentcan be insoluble to very soluble in the temperature-sensitive materialhoused in the delivery system 10. The amount of agent present in adelivery system 10 can be from 10 ng to 40 g or more. The deliverysystem can house various amounts of the beneficial agent, for example,75 ng, 1 mg, 5 mg, 100 mg, 250 mg, 750 mg, 1.5 mg, 2 g, 5 g, 10 g, 15 g,and the like. A single delivery system can be administered to an animal,or more than one delivery system can be administered to an animal duringa therapeutic program.

Representative of beneficial medicaments 18 that can be dispensed usingthe delivery system of this invention include anthelmintics such asmebendazole, levamisole, albendazole, cambendazole, fenbendazole,parbendazole, oxfendazole, oxybendazole, thiabendazole, trichlorfon,praziquantel, morantel and pirantel, and the like; antiparasitic agentssuch as avermectins and ivermectin, as disclosed in U.S. Pat. Nos.4,199,569 and 4,389,397 both assigned to Merck & Co., and in Science,Vol. 221, pages 823 to 828, 1983, wherein said invermectin antiparasiticdrug are disclosed as useful for aiding in controlling commonlyoccurring infestations in animals, such as roundworms, lung worms andthe like, and said invermectin also being useful for the management ofinsect infestations such as grub, lice, mange mite, and the like;antimicrobial agents such as chlortetracycline, oxytetracycline,tetracycline, streptomycin, dihydrostreptomycin, bacitracins,erythromycin, ampicillins, penicillins, cephalosporins, and the like;sulfa drugs such as sulfamethazine, sulfathiazole, and the like;growth-stimulants such as Monesin® sodium and Elfazepa®; defleaingagents such as dexamethasone and flumethasone; rumen fermentationmanipulators and ionophores such as lasalocid, virginiamycin and ronnel;minerals and mineral salts; anti-bloat agents such as organopolysiloxanes; hormone growth supplements such as stilbestrol; vitamins;antienteritis agents such as furazolidone; nutritional supplements suchas lysine monohydrochloride, methionine, magnesium carbonate; sodiumselenite, cobalt, and the like.

Representative of inert viscosity-inducing compound 19 used by thepresent invention to increase the viscosity and/or the yield stress of athermo-responsive composition are compounds containing silicon, such asfumed silica, reagent grade sand, precipitated silica, amorphous silica,colloidal silicon dioxide, fused silica, silica gel, quartz, particulatesiliceous materials commercially available as Syloid®, Cabosil®,Aerosil®, Whitelite®, and the like. Other inert compounds includeprecipitated calcium carbonate, aluminum carbonate, manganesefluosilicate, manganese pyroselenite, nickel sulfite, potassiumsilicate, and the like. The viscosity- or stress-inducing agent in apresently preferred embodiment is soluble or miscible or dispensable inthe heat-sensitive formulation and it can be homogeneously orheterogeneously blended or dispersed therein. The term "viscosity" asused herein denotes the property of a fluid, semifluid, or viscous statethat enables it to develop and maintain an amount of shearing stressdependent upon the velocity of flow and then to offer continuedresistance to flow. The expression "yield stress" as used hereingenerically denotes an increased internal stress of the heat sensitiveformulation to the point that strain yields, that is the point where theheat-sensitive formulation begins to flow. The amount of inert,nontoxic, pharmaceutically acceptable compound used for the presentpurpose usually is about 0.01% by weight to about 35% by weight.

The dense member 22, also referred to as densifier or density element22, optionally used in the delivery system of this invention is denseenough to retain system 10 in the rumen-reticular sac of a ruminant.Dense member 22 lets system 10 remain in the rumen over a prolongedperiod of time rather than letting it pass into the alimentary tract andbe eliminated therefrom. As delivery system 10 remains in the rumen,beneficial active agent 18 is delivered by delivery system 10 at acontrolled rate to the ruminant over time. Generally, dense member 20will have a density of from about 0.8 to 8, or higher, with the densityin a presently preferred embodiment exhibiting a specific gravity offrom 1.2 to 7.6. For the ruminants cattle and sheep, it is presentlypreferred dense member 22 exhibit a density such that there is aresulting system density of about 3. Materials that have a density thatcan be used for forming dense member 22 include iron, iron shot, ironshot coated with iron oxide, iron shot magnesium alloy, steel, stainlesssteel, copper oxide, a mixture of cobalt oxide and iron powder, and thelike. Dense member 22 in delivery system 10 can embrace differentembodiments. For example, dense member 22 as seen in FIG. 2 is machinedor cast as a single, solid piece made of stainless steel having adensity of 7.6. The solid member 22 is made having a curved shape thatcorresponds to the internal shape of delivery system 10. The solidmember as seen in FIG. 2 has an axially aligned bore that extendsthrough the length of the unit member that serves as a passageway forletting thermo-responsive composition 17 comprising beneficial agent 18leave lumen 16 and be dispensed through exit member 25 to the rumen. Inanother embodiment, dense member 22 is manufactured as a solid body asseen in FIG. 4. Density member 22, as seen in FIG. 6, can be dispersedthroughout an expandable member 20. In this latter manufacture, adensity-increasing member is homogeneously or heterogeneously dispersedthroughout the expandable hydrogel for initially retaining deliverysystem 10 in the rumen-reticular sac of a ruminant. Material that have adensity of from 1 to 8 that can be blended with the hydrogel expandablemember include iron particles, iron shot, iron shot coated with ironoxide, a mixture of iron and copper oxide powder, and the like. Theweight can be blended with the hydrogel during polymerization, byblending solvent casting and evaporating, by compressing a blend, andthe like. The amount of weight means blended with a hydrogel is about0.5 to 70 weight percent, or an amount sufficient to produce the desireddensity. Density, specific gravity and specific volume determination areeasily performed by procedures known in the art as disclosed inRemington's Pharmaceutical Sciences, Vol. 14, pp 95-100, edited by Osol,1970, by Mack Publishing Co., Easton, Pa.

Partition layer 31, as seen in FIG. 9, is positioned between the activeformulation 17 and the expandable driving member 20. Partition layer 31substantially maintains the separate identity of the thermo-responsivecomposition containing the beneficial agent and the expandable member,and in a presently preferred embodiment layer 31 is a wax. The term"wax" as used herein generically denotes a petroleum-based food-gradewax or an ester of a high molecular weight alcohol. Materials useful forthis purpose include waxes, which are a different wax composition than awax comprising the thermo-responsive composition; for example, theformer can be a higher melting point wax. The waxes acceptable for thispresent purpose exhibit a melting point or a solidification point ofabout 45° C. to 110° C. and they are selected from the group consistingof mineral, vegetable, plant, animal, petroleum, and synthetic waxes.Representative waxes include a member selected from the group includingthe following wax and its melting range: montan wax, 80°-90° C.,ozokerite wax, 55°-110° C., usually 70° C.; carnauba wax, 84°-86° C.;myricyl cerotate wax, 85° C.; beeswax, 63° C.; spermaceti, 45° C.;ceresin wax, 48° C.; gama wax, 47° C.; Japan wax, 63° C.; ouricury wax,83° C.; ceresin wax, 68°-72° C.; castor wax, 85° C.; Witco wax, 72° C.;microcrystalline petroleum wax, 66°-88° C. and the like. Additionally,reinforcing agents such as Cab-o-sil can be incorporated into the waxfor improving structural integrity.

Partition layer 31 optionally comprises a film-forming polymer that iscapable of receiving and transmitting an applied force, such as olefinpolymers, vinyl polymers, synthetic condensation polymers, naturalpolymers, and organosilicon polymers. Representative of specificpolymers include polyethylene, polypropylene, polytetrafluoroethylene,polystyrene, polyvinyl acetate, polyvinyl formal, cross-linked polyvinylacetate, polyvinyl butyral polyacrylate, polymethyacrylate,polyvinylchloride, cellulose acetate, polyamides, polyester, rubber,styrene butadiene rubber, polyurethane, polysilicone, and the like. Thelamina can have a thickness from 1 mil (0.0254 mm) to 590 mil (15 mm),or more, for effectively transmitting the in vivo generated force.

Wall 12 of delivery system 10 can be made by conventional thermoformingpolymeric processes, such as spraying a mandrel, dipping a mold into awall forming composition, blow molding, vacuum forming, compressionmolding, injection molding, extrusion and the like.

Exemplary solvents suitable for manufacturing the walls include inertinorganic and organic solvents that do not adversely harm the materials,the wall, the beneficial agent, and other components comprising thefinal dispenser. The solvents broadly include a member selected from thegroup consisting of aqueous, alcohol, ketone, ester, ether, aliphatichydrocarbon, halogenated, cycloaliphatic, aromatic, and heterocyclicsolvents, and mixtures thereof. Solvents for the present purpose aredisclosed in U.S. Pat. Nos. 4,729,793 and 4,772,474 by Eckenhoff,Cortese and Landrau.

DISCLOSURE OF EXAMPLES OF THE INVENTION EXAMPLE 1

A delivery system manufactured in the shape of a dispenser adapted forthe controlled delivery of ivermectin to an animal is made as follows:first, a semipermeable membrane cup in the shape of a dispenser isinjection molded from a wall-forming composition comprising 50.5%cellulose acetate butyrate 171-15 having a 17.1% butyryl content, a29.5% acetyl content and a 1.5% hydroxyl content; 17.5% celluloseacetate 398-10 having a 39.8% acetyl content; 22% Citroflex® 4 tributylcitrate, 6% Citroflex® 2 triethyl citrate and 4% polyethylene glycol400. The final injection molded cup weighed about 10 grams each.

Next, an expandable driving member designed as an osmotic tablet ismanufactured in a shape that corresponds to the internal shape of theinjection molded cup. The expandable driving member compositioncomprises 2.5 g of sodium chloride, 5.8 g of the sodium salt ofpolyacrylic acid polymer available as Carbopol® 934P, 0.07 g ofPovidone® polyvinyl pyrrolidone, and 0.10 g of magnesium stearate. Thecomposition was compressed under 10 tons into an osmotic tablet, 0.850inches in diameter, 0.66 inches in height, and having a tablet densityapproximately 1.56 g/cc.

Next, 600 g of ivermectin was added with high shear mixing at 90° C. to3400 g of pharmaceutically acceptable wax exhibiting a melting point of150°/160° F., a Saybolt viscosity of 75/90 at 210° F., and a lightyellow color. The two ingredients were blended at 90° C. for about 30minutes. The high shear mixing was turned off and the anchor blade andimpeller blade activated at 35% speed to ensure a homogenous blend.Then, a vacuum, 10 inches of Hg, was pulled for 30 minutes and themixture cooled to 74° C., after which the impeller blade was turned offand the vacuum released. The mixing tank then was pressurized to 5 psig.using nitrogen.

Next, 500 g of microcrystalline wax exhibiting a melting point of150°/160° F., a needle penetration at 77° F. of 35/45, and a Sayboltviscosity of 75/90 at 210° F. was added to 500 g of microcrystalline waxexhibiting a melting point of 180°/190° F., a needle penetration of15/20 at 77° F. and a Saybolt viscosity of 75/90 at 210° F. and the twoingredients were blended at 90° C. to form a homogenous blend. The blendis designed for use as a partition formulation and the blend was madeusing a high shear rotor stator blade. After 10 minutes of mixing, therotor stator blade was turned off and a vacuum pulled on the resultingmixture for about 30 minutes.

The dispenser was assembled by first placing the osmotic expansiontablet into the membrane cup. The membrane cup was preheated at 60° C.for about 5 minutes. Next, 1.95 g of the partition formulation was addedto the membrane cup in contacting relation with the osmotic expansiontablet. After cooling for 2 to 6 minutes, 9.5 g of the formulationcomprising the ivermectin was added to the membrane cup, followed bycooling the cup to 60° C. for 8 minutes. Then, a density elementcomprising iron with a central bore and dimensioned to conform to theinside of the membrane cup was placed into the cup. The density elementwas preheated to 65° C., and inserted into the membrane cup until thebottom of the density element contacted the thermo-responsive ivermectinformulation.

Next, the membrane cup was rotated in front of a hot air gun until thetip of the membrane softened and became thermoplastic. The membrane cupnext was placed into a crimping fixture pressurized with 90 psi,compressed air, followed by a crimping head activated, positioned androtated on top of the membrane cup for 15 seconds to yield thedispenser. Accompanying FIG. 12 depicts the release rate patterns forivermectin for a dispenser made by this example.

EXAMPLE 2

A delivery system manufactured in the shape of a dispenser adapted foradministering a beneficial agent to an animal was made by following theprocedure of Example 1. The delivery system was made as described,except as follows: 600 g of ivermectin was added with high shear mixingat 90° C. to 3320 g of microcrystalline food grade wax having a meltingpoint of 150°-160° F. and a Saybolt viscosity at 210° F. of 75/90, and80 g of silicon dioxide. The silicon dioxide increases the viscosity andyield stress of the ivermectin-containing formulation. The threeingredients were blended with a rotor stator blade at 90° C. for 30minutes. Then, the high shear mixing was turned off and the anchor andimpeller blades were activated at 35% speed followed by pulling 10inches of Hg vacuum for 30 minutes. Then, the mixture was cooled toapproximately 74° C., the impeller blade turned off and the vacuumreleased. Next, the mixing tank was pressurized to 5 psi using nitrogengas.

Next, 490 g of food grade microcrystalline wax, as described in theparagraph immediately above, was added to 490 g of a food grademicrocrystalline wax having a 180°-190° F. melting point and a Sayboltviscosity at 210° F. of 75/90, and the mixture heated to 90° C. Then, 20g of silicon dioxide was added to the molten waxes and the mixtureblended using a high shear rotor stator blade for 10 minutes. After 10minutes of mixing, the high shear rotor stator blade was turned off and10 inches of Hg pulled on the mixture for 30 minutes. The dispenser wasassembled as described in Example 1. Accompanying FIG. 13 illustratesthe in vivo release rate profile for the dispenser made according tothis example. The addition of the silicon dioxide improved theuniformity of the release rate profile over that of FIG. 12.

EXAMPLE 3

A delivery system manufactured in the shape of a dispenser for thecontrolled delivery of the beneficial agent ivermectin was madeaccording to the procedures of Example 2. In this example, an exitmember made as a stainless steel grid with a plurality of openings ofapproximately 18 mesh was placed in the exit bore of the densityelement. The wall of the membrane cup was crimped as described above.Accompanying FIG. 14 depicts the release rate profile for the dispensermade according to this Example. The placement of the stainless steelgrid has significantly improved the uniformity of the release rateprofile over that of FIGS. 12 and 13.

EXAMPLE 4

A delivery system for the controlled delivery of the beneficial agentivermectin was made according to the procedure of Example 2, with allprocedures as described except for the manufacturing steps described inthis example. In this example 1% of titanium dioxide was dry blendedinto the composition comprising the membrane cup. The membrane cup wasinjected molded using the procedures set forth in Example 1. Thestainless steel exit member of Example 3 was replaced with a polymericexit member manufactured from nylon as seen in drawing FIGS. 3a, 3b, 3c,and 9. The uniform release rate profile from the dispenser madeaccording to this example is illustrated in FIG. 15.

EXAMPLE 5

A delivery system for the controlled delivery of the beneficial drugivermectin with instant start-up was made as set forth in Example 4,except as follows: the delivery system of Example 4 was prehydrated for18 days at 40° C. in deionized water, after which the prehydrationtemperature was ramped down over 8 days at approximately 2°-3° C. perday. The delivery system was packaged and stored for at least one weekprior to use. The delivery system can be prehydrated with a permeant byimmersing, partial immersion, dipping, spraying, or the like in apermeant such as water, distilled water, a buffer, a physiologicallyacceptable fluid such as saline or the like. The delivery system can beprehydrated with a permeant for 1 hr. to 18 days or longer, at anytemperature usually at 20° C. to 40° C. or the like. The prehydration isprovided to reduce drug delivery start-up time, or to provide instantdrug delivery, especially when delivered to an animal. Sometimes,dependent on the manufacture, the delivery system exhibits a 2 to 3 weekstart-up, while a prehydrated delivery system begins to deliver drugduring the first week, usually starting in 24 hours. The volume ofprehydration permeant introduced into a delivery system is usually about0.025 g to 10 g of permeant, and more preferably from 0.1 g to 3 g ofpermeant. The amount of permeant imbibed into a delivery system usuallyis greater than 1% by weight of the displacement means, and in apresently preferred amount of about 5% to 40% of the weight of thedisplacement means. FIG. 16 depicts the in vivo release rate for adelivery system made according to this procedure.

EXAMPLES 6 TO 11

Delivery systems were made according to the above described procedures.In the following examples, the delivery profile for delivery systemswere measured in different test environments. The test environments werein vitro and in vivo. The in vitro test environments included water,artificial ruminal fluid sparged with a 50/50% mixture of nitrogen andcarbon dioxide, artificial ruminal fluid sparged with 25/75%nitrogen/carbon dioxide, and an in vivo environment of a fistulated cow.

The release rate pattern for delivery systems is illustrated in thefollowing drawing figures. Drawing FIG. 17 depicts the release ratepatterns from a delivery system comprising a drug load of 15% ivermectinand a 0.150 inch bore through the density member as measured inartificial ruminal fluid containing 75% carbon dioxide; drawing FIG. 18depicts the release rate pattern from a delivery system comprising a 15%drug load of ivermectin, a 0.200 inch bore through the density membercovered with a mesh screen and measured in artificial ruminal fluidcontaining 75% carbon dioxide; drawing FIG. 19 depicts the release rateprofile from a delivery system comprising a 15% load of ivermectin, 2%silicon dioxide, a 0.150 inch bore and measured in artificial ruminalfluid containing 75% carbon dioxide; drawing FIG. 20 depicts the releaserate pattern from a delivery system comprising 15% ivermectin, a 0.200inch bore covered by a mesh screen and measured in vivo; drawing FIG. 21depicts the release rate pattern from a delivery device comprising 15%ivermectin, 2% silicon dioxide, a 0.200 inch bore covered with apressure inducing screen and measured in artificial ruminal fluidcomprising 75% carbon dioxide; drawing FIG. 22 depicts the release ratepattern from a delivery system comprising a 15% drug load, 2% of silicondioxide, a 0.200 inch bore with a screen and the measurements made invivo. Accompanying FIGS. 18 to 22 all represent improvements over therelease rate profile of FIG. 17.

DISCLOSURE OF METHOD OF USING THE INVENTION

An embodiment of the invention pertains to a method for administering toa warm blooded animal a beneficial drug at a controlled rate, whichmethod comprises the steps of: (A) admitting into an animal in need of abeneficial drug an improved dispensing device comprising: (1) a wallcomprising in at least a part a semipermeable polymeric compositionpermeable to the passage of fluid and substantially impermeable to thepassage of drug, the wall surrounding (2) an internal lumen comprising athermo-responsive composition comprising a dosage unit amount of abeneficial drug, said thermo-responsive composition softening andforming at animal body temperature a dispensable formulation that is ameans for transporting the drug from the dispenser; (3) an expandabledriving member in the lumen for pushing or otherwise displacing thethermo-responsive composition from the dispenser; (4) an optional densemember for keeping the dispenser, when in a rumen, in the animal over aprolonged period of time; and (5) an exit opening in the wall; whereinthe improvement comprises (a) an exit member in the exit opening forincreasing the pressure in the device and for increasing the hydraulicresistance to flow in the wall communicating with the lumen, and/or (b)a viscosity-inducing agent in the thermo-responsive composition forincreasing the viscosity and/or yield stress of the thermo-responsivecomposition; (B) imbibing fluid through the semipermeable wall at a ratedetermined by the permeability of the semipermeable wall and the osmoticpressure gradient across the semipermeable wall to cause the drivingmember to increase in volume; (C) softening the thermo-responsivecomposition to form a dispensable flowable formulation; and (D)delivering the beneficial drug from the dispenser by the driving membercontinually displacing the dispensable formulation through the exitmember in a therapeutically effective amount at a controlled, consistentand predictable rate to the animal over a prolonged period of time from1 day to 350 days or longer. The dispenser may be admitted orally to theanimal or it may be implanted subcutaneously or interperitoneally intothe animal.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made herein in accordance with the inventive principles disclosed,without departing from the scope of the invention.

What is claimed is:
 1. An improved delivery system for administering abeneficial agent to an environment of use, the delivery systemcomprising:i) a wall that surrounds a lumen, the wall comprising in atleast a part a semipermeable composition, ii) a thermo-responsivecomposition in the lumen that forms a dispensable formulation at thetemperature of the environment of use, iii) a beneficial agent mixedwith the thermo-responsive composition, iv) an expandable driving memberin the lumen for displacing the thermo-responsive composition from thedelivery system, and v) an exit opening in the wall that communicateswith the lumen;wherein, the improvement comprises: a) aviscosity-inducing amount of an inert viscosity-inducing agent in thethermo-responsive composition for increasing the viscosity of thethermo-responsive composition, and b) a pressure-inducing exit member inthe exit opening in the wall for increasing the pressure inside thelumen, the exit member having from 1 to exit ports or passageways;wherein the delivery system when in operation develops an internalpressure such that the pressure differential generated by thethermo-responsive composition and the exit member is greater than 1.5psi.
 2. An improved delivery system according to claim 1 wherein theviscosity-inducing agent comprises silicon.
 3. An improved deliverysystem according to claim 1 wherein the viscosity-inducing agent isselected from the group consisting of silica, sand, precipitated silica,amorphous silica, silicon dioxide, colloidal silicon dioxide, fusedsilica, fumed silica, quartz, silica gel, and a siliceous composition.4. An improved delivery system according to claim 1 wherein theviscosity-inducing agent increases the stress to flow of thethermo-responsive composition.
 5. An improved delivery system accordingto claim 1 wherein the exit member is a releasable pressure-inducingexit member positioned in the exit opening in the wall.
 6. An improveddelivery system according to claim 1 where n the exit member is aninsert for placement in the exit opening in the wall of the dispenser.7. An improved delivery system according to claim 1 where n the exitmember is selected from a grid, a perforated plate, a plurality ofcapillaries, and a plurality of tubes.
 8. An improved delivery systemaccording to claim 6 wherein the exit member is selected from a grid, aperforated plate, a plurality of capillaries, and a plurality of tubes.9. An improved delivery system according to claim 1 wherein thebeneficial agent is avermectin or ivermectin.
 10. An improved deliverysystem according to claim 1 wherein the driving member comprises anosmagent, an osmopolymer or an osmagent together with an osmopolymer.11. An improved delivery system according to claim 1 wherein thedispenser further comprises an inert partition layer in the lumenbetween the thermo-responsive composition and the driving member.
 12. Animproved delivery system according to claim 1 wherein the deliverysystem further comprises a density member in the lumen for maintainingthe delivery system in the environment of use over time, the densitymember having a density greater than the density of the environment ofuse.
 13. An improved delivery system according to claim 12 wherein thedensity member comprises a weight with a bore in the weight, and theexit member is in contact with the bore.
 14. An improved delivery systemaccording to claim 1 wherein the environment of use is an animal.
 15. Animproved delivery system according to claim 12 wherein the environmentof use is a ruminant animal.
 16. An improved delivery system foradministering a beneficial agent to an environment of use, the deliverysystem comprising:i) a wall that surrounds a lumen, ii) athermo-responsive composition in the lumen, iii) a beneficial agentmixed with the thermo-responsive composition, iv) an expandable drivingmember in the lumen for displacing the thermo-responsive compositionfrom the dispenser, and v) an exit opening in the wall that communicateswith the lumen;wherein, the improvement comprises: a) aviscosity-inducing amount of an inert viscosity-inducing agent mixedinto the thermo-responsive composition for increasing the viscosity ofthe thermo-responsive composition to increase the internal pressure ofthe dispenser; wherein the delivery system when in operation develops aninternal pressure such that the pressure differential generated by thethermo-responsive composition and the exit opening is greater than 1.5psi.
 17. An improved delivery system according to claim 16 wherein theviscosity-inducing agent comprises silicon.
 18. An improved deliverysystem according to claim 16 wherein the viscosity-inducing agent isselected from the group consisting of silica, sand, precipitated silica,amorphous silica, silicon dioxide, colloidal silicon dioxide, fusedsilica, fumed silica, quartz, silica gel, and a siliceous composition.19. An improved delivery system according to claim 16 wherein theviscosity-inducing agent increases the stress to flow of thethermo-responsive composition.
 20. An improved delivery system accordingto claim 16 wherein the dispenser further comprises an inert partitionlayer in the lumen between the thermo-responsive composition and thedriving member.
 21. An improved delivery system according to claim 16wherein the delivery system further comprises a density member in thelumen for maintaining the delivery system in the environment of use overtime, the density member having a density greater than the density ofthe environment of use.
 22. An improved delivery system foradministering a beneficial agent to an environment of use, the deliverysystem comprising:i) a wall that surrounds a lumen, ii) athermo-responsive composition in the lumen, iii) a beneficial agentmixed with the thermo-responsive composition, iv) an expandable drivingmember in the lumen for displacing the thermo-responsive compositionfrom the dispenser, and v) an exit opening in the wall that communicateswith the lumen;wherein, the improvement comprises: a) apressure-inducing exit member in the exit opening in the wall forincreasing the pressure inside the lumen, the exit member having from 1to 200 exit ports or passageways; wherein the delivery system when inoperation develops an internal pressure such that the pressuredifferential generated by the thermo-responsive composition and the exitmember is greater than 1.5 psi.
 23. An improved delivery systemaccording to claim 22 wherein the exit member is a releasablepressure-inducing exit member.
 24. An improved delivery system accordingto claim 22 wherein the exit member is an insert for placement in theexit opening in the wall of the delivery system.
 25. An improveddelivery system according to claim 22 wherein the exit member isselected from a grid, a perforated plate, a plurality of capillaries,and a plurality of tubes.
 26. An improved delivery system according toclaim 24 wherein the exit member is selected from a grid, a perforatedplate, a plurality of capillaries, and a plurality of tubes.
 27. Animproved delivery system according to claim 22 wherein the dispenserfurther comprises an inert partition layer in the lumen between thethermo-responsive composition and the driving member.
 28. An improveddelivery system according to claim 22 wherein the delivery systemfurther comprises a density member in the lumen for maintaining thedelivery system in the environment of use over time, the density memberhaving a density greater than the density of the environment of use. 29.An improved delivery system according to claim 28 wherein the densitymember comprises a weight with a bore in the weight, and the exit memberis in contact with the bore.